Beta-cell specific production of IL6 in conjunction with a mainly intracellular but not mainly surface viral protein causes diabetes.

Inflammatory mechanisms play a key role in the pathogenesis of type 1 and type 2 diabetes. IL6, a pleiotropic cytokine with impact on immune and non-immune cell types, has been proposed to be involved in the events causing both forms of diabetes and to play a key role in experimental insulin-dependent diabetes development. The aim of this study was to investigate how beta-cell specific overexpression of IL-6 influences diabetes development. We developed two lines of rat insulin promoter (RIP)-lymphocytic choriomeningitis virus (LCMV) mice that also co-express IL6 in their beta-cells. Expression of the viral nucleoprotein (NP), which has a predominantly intracellular localization, together with IL6 led to hyperglycemia, which was associated with a loss of GLUT-2 expression in the pancreatic beta-cells and infiltration of CD11b(+) cells, but not T cells, in the pancreas. In contrast, overexpression of the LCMV glycoprotein (GP), which can localize to the surface, with IL-6 did not lead to spontaneous diabetes, but accelerated virus-induced diabetes by increasing autoantigen-specific CD8(+) T cell responses and reducing the regulatory T cell fraction, leading to increased pancreatic infiltration by CD4(+) and CD8(+) T cells as well as CD11b(+) and CD11c(+) cells. The production of IL-6 in beta-cells acts prodiabetic, underscoring the potential benefit of targeting IL6 in diabetes.

Development of autoimmune diabetes in the absence of detectable IL-17A in a CD8-driven virally induced model.

Recent studies have shown that IL-17 can contribute beneficially to pathogen defense but also that excessive IL-17 levels are associated with chronic inflammation and autoimmune disorders. To date, the role of IL-17 in viral infections and type 1 diabetes is ambiguous. In this study, we used IL-17A enhanced green fluorescent protein bicistronic reporter mouse strains to analyze in situ production of IL-17A. Upon Klebsiella pneumoniae bacterial infection, CD4(+) and γδ T cells produce IL-17A. In contrast, CD4(+) or CD8(+) T cells do not produce IL-17A in response to acute or protracted viral infection with lymphocytic choriomeningitis virus or during autoimmune diabetes development in the CD8-driven lymphocytic choriomeningitis virus-induced model of type 1 diabetes. We conclude that viral elimination and type 1 diabetes can occur in the absence of detectable IL-17A production, suggesting IL-17A is not essential in these settings.

Pre-existing autoimmunity determines type 1 diabetes outcome after Flt3-ligand treatment.

Redirection of immune responses by manipulation of antigen-presenting cells is an emerging strategy for immunosuppressive treatment of autoimmune diseases. In vivo expansion of dendritic cells (DC) by Fms-like tyrosine kinase-3 (Flt3)-Ligand (FL) treatment was shown to delay diabetes onset in the NOD model of autoimmune diabetes. However, we show here that Flt3 stimulation actually accelerates autoimmunity when autoreactive CD8 T cells are detectable in blood prior to treatment. With autoreactive CD8 cells present, the capacity of FL to expand DCs and induce Treg remained intact, but both numbers and the functional response of islet-specific CD8s were boosted. Also, the inhibitory receptor PD-1 on (autoreactive) CD8 T cells and its ligand PD-L1 on Treg were no longer upregulated. These data highlight the need to pre-screen for T cell autoreactivity prior to generalized DC expansion and illustrate how accelerated disease can occur when the intended initiation of regulatory mechanisms is impaired later in diabetogenesis.